During the course of chronic hepatitis B virus (HBV) infection, hepatitis B e antigen (HBeAg) seroconversion to its antibody (anti-HBe) often coincides with normalization of liver biochemical test and clinical remission, but data regarding long-term outcome after spontaneous seroconversion are still scarce. Excluding patients with other virus(es) concurrent infection, 283 patients with chronic HBV infection were followed up for at least 1 year after spontaneous HBeAg seroconversion to anti-HBe. Follow-up studies included clinical, biochemical, and virologic evaluation and hepatocellular carcinoma (HCC) screening with ultrasonography and alpha-fetoprotein assay. During a median follow-up period of 8.6 years (range, 1 to 18.4 years) after HBeAg seroconversion in 283 patients, 189 (66.8%) showed sustained remission, whereas the remaining 94 (33.2%) experienced alanine aminotransferase (ALT) elevation over twice the upper limit of normal: 12 (4.2%) associated with HBeAg reversion, 68 (24%) with detectable serum HBV DNA but HBeAg negative, and 14 (4.9%) of undetermined causes. Of the 269 patients without evidence of cirrhosis at the time of HBeAg seroconversion, 21 (7.8%) developed cirrhosis with a cumulative incidence and relative risk significantly higher in patients developing active hepatitis than in patients with sustained remission (P <.05). HCC developed in 6 (2.2%) of the 283 patients, also with a significantly higher cumulative incidence in patients developing active hepatitis after HBeAg seroconversion (P <.005). In conclusion, the results suggest that spontaneous HBeAg seroconversion confers favorable long-term outcomes. However, active hepatitis still may develop and lead to cirrhosis and HCC.